The present invention relates to new and useful oxazolidinone compounds and their preparations, and more particularly to oxazolidinone compounds in which the carbonyl functionality of xe2x80x94NHxe2x80x94C(O)xe2x80x94R is converted to a thiocarbonyl functionality, such as a thiourea xe2x80x94NHxe2x80x94C(S)xe2x80x94NH2, an alkyl thiourea xe2x80x94NHxe2x80x94C(S)xe2x80x94NHxe2x80x94(C1-4 alkyl), thioamide xe2x80x94NHxe2x80x94C(S)xe2x80x94(C1-4 alkyl) or xe2x80x94NHxe2x80x94C(S)xe2x80x94H.
Replacement of the oxygen atom with a sulfur atom has unexpectedly improved the antimicrobial properties of the compounds. The compounds are useful antimicrobial agents, effective against a number of human and veterinary pathogens, including Gram-positive aerobic bacteria such as multiply-resistant staphylococci and streptococci, Gram-negative organisms such as H. influenzae and M. catarrahlis as well as anaerobic organisms such as bacteroides and clostridia species, and acid-fast organisms such as Mycobacterium tuberculosis and Mycobacterium avium. The compounds are particularly useful because they are effective against the latter organisms which are known to be responsible for infection in persons with AIDS.
In one aspect the subject invention is a compound of the Formula I 
or pharmaceutical acceptable salts thereof wherein:
G is 
R1 is
a) H,
b) NH2,
c) NHxe2x80x94C1-4 alkyl,
d) C1-4 alkyl,
e) xe2x80x94OC1-4 alkyl,
f) xe2x80x94S C1-4 alkyl,
g) C1-4 alkyl substituted with 1-3 F, 1-2 Cl, CN or xe2x80x94COOC1-4 alkyl,
h) C3-6 cycloalkyl,
i) N(C1-4alkyl)2 or
j) N(CH2)2-5;
A is 
d) a 5-membered heteroaromatic moiety having one to three atoms selected from the group consisting of S, N, and O,
xe2x80x83wherein the 5-membered heteroaromatic moiety is bonded via a carbon atom,
xe2x80x83wherein the 5-membered heteroaromatic moiety can additionally have a fused-on benzene or naphthyl ring,
xe2x80x83wherein the heteroaromatic moiety is optionally substituted with one to three R48,
e) a 6-membered heteroaromatic moiety having at least one nitrogen atom,
xe2x80x83wherein the heteroaromatic moiety is bonded via a carbon atom,
xe2x80x83wherein the 6-membered heteroaromatic moiety can additionally have a fused-on benzene or naphthyl ring,
xe2x80x83wherein the heteroaromatic moiety is optionally substituted with one to three R55,
f) a xcex2-carbolin-3-yl, or indolizinyl bonded via the 6-membered ring, optionally substituted with one to three R55, 
wherein
R2 is
a) H,
b) F,
c) Cl,
d) Br,
e) C1-3 alkyl,
f) NO2, or
g) R2 and R3 taken together are xe2x80x94Oxe2x80x94(CH2)hxe2x80x94Oxe2x80x94;
R3is
a) xe2x80x94S(xe2x95x90O)iR4,
b) xe2x80x94S(xe2x95x90O)2xe2x80x94Nxe2x95x90S(O)jR5R6,
c) xe2x80x94SC(xe2x95x90O)R7,
d) xe2x80x94C(xe2x95x90O)R8,
e) xe2x80x94C(xe2x95x90O)R9,
f) xe2x80x94C(xe2x95x90O)NR10R11,
g) xe2x80x94C(xe2x95x90NR12)R8,
h) xe2x80x94C(R8)(R11)xe2x80x94OR13,
i) xe2x80x94C(R9)(R11)xe2x80x94OR13,
j) xe2x80x94C(R8)(R11)xe2x80x94OC(xe2x95x90O)R13,
k) xe2x80x94C(R9)(R11)xe2x80x94OC(xe2x95x90O)R13,
l) xe2x80x94NR10R11,
m) xe2x80x94N(R10)xe2x80x94C(xe2x95x90O)R7,
n) xe2x80x94N(R10)xe2x80x94S(xe2x95x90O)iR7,
o) xe2x80x94C(OR14)(OR15)R8,
p) xe2x80x94C(R8)(R16)xe2x80x94NR10R11, or
q) C1-8 alkyl substituted with one or more xe2x95x90O other than at alpha position, xe2x80x94S(xe2x95x90O)iR17, xe2x80x94NR10R11, C2-5 alkenyl, or C2-5 alkynyl;
R4 is
a) C1-4 alkyl optionally substituted with one or more halos, OH, CN, NR10R11, or xe2x80x94CO2R13,
b) C2-4 alkenyl,
c) xe2x80x94NR16R18,
d) xe2x80x94N3,
e) xe2x80x94NHC(xe2x95x90O)R7,
f) xe2x80x94NR20C(xe2x95x90O)R7,
g) xe2x80x94N(R19)2,
h) xe2x80x94NR16R19, or
i) xe2x80x94NR19R20,
R5 and R6 at each occurrence are the same or different and are
a) C1-2 alkyl, or
b) R5 and R6 taken together are xe2x80x94(CH2)kxe2x80x94;
R7 is C1-4 alkyl optionally substituted with one or more halos;
R8 is
a) H, or
b) C1-8 alkyl optionally substituted with one or more halos, or C3-8 cycloalkyl;
R9 is C1-4 alkyl substituted with one or more
a) xe2x80x94S(xe2x95x90O)R17,
b) xe2x80x94OR13,
c) xe2x80x94OC(xe2x95x90O)R13,
d) xe2x80x94NR10R11, or
e) C1-5 alkenyl optionally substituted with CHO;
R10 and R11 at each occurrence are the same or different and are
a) H,
b) C1-4 alkyl, or
c) C3-8 cycloalkyl;
R12 is
a) xe2x80x94NR10R11,
b) xe2x80x94OR10; or
c) xe2x80x94NHC(xe2x95x90O)R10;
R13 is
a) H, or
b) C1-4 alkyl;
R14 and R15 at each occurrence are the same or different and are
a) C1-4alkyl, or
b) R14 and R15 taken together are xe2x80x94(CH)1xe2x80x94;
R16 is
a) H,
b) C1-4 alkyl, or
c) C3-8 cycloalkyl;
R17 is
a) C1-4 alkyl, or
b) C3-8 cycloalkyl;
R18 is
a) H,
b) C1-4 alkyl,
c) C2-4 alkenyl,
d) C3-4cycloalkyl,
e) xe2x80x94OR13 or
f) xe2x80x94NR21R22;
R19 is
a) Cl,
b) Br, or
c) I;
R20 is a physiologically acceptable cation;
R21 and R22 at each occurrence are the same or different and are
a) H,
b) C1-4 alkyl, or
c) xe2x80x94NR21R22 taken together are xe2x80x94(CH2)mxe2x80x94;
wherein
R23 and R24 at each occurrence are the same or different and are
a) H,
b) F,
c) Cl,
d) C1-2 alkyl,
e) CN
f) OH,
g) C1-2 alkoxy,
h) nitro, or
i) amino;
Q is 
m) a diazinyl group optionally substituted with X and Y,
n) a triazinyl group optionally substituted with X and Y,
o) a quinolinyl group optionally substituted with X and Y,
p) a quinoxalinyl group optionally substituted with X and Y,
q) a naphthyridinyl group optionally substituted with X and Y, 
Q and R24 taken together are 
wherein Z1 is
a) xe2x80x94CH2xe2x80x94,
b) xe2x80x94CH(R104)xe2x80x94CH2xe2x80x94,
c) xe2x80x94C(O)xe2x80x94, or
d) xe2x80x94CH2CH2CH2xe2x80x94;
wherein Z2 is
a) xe2x80x94O2Sxe2x80x94,
b) xe2x80x94Oxe2x80x94,
c) xe2x80x94N(R107)xe2x80x94,
d) xe2x80x94OSxe2x80x94, or
e) xe2x80x94Sxe2x80x94;
wherein Z3 is
a) xe2x80x94O2Sxe2x80x94,
b) xe2x80x94Oxe2x80x94,
c) xe2x80x94OSxe2x80x94, or
d) xe2x80x94Sxe2x80x94;
wherein A1is
a) Hxe2x80x94, or
b) CH3;
wherein A2 is
a) Hxe2x80x94,
b) HOxe2x80x94,
c) CH3xe2x80x94,
d) CH3Oxe2x80x94,
e) R102Oxe2x80x94CH2xe2x80x94C(O)xe2x80x94NHxe2x80x94
f) R103xe2x80x94Oxe2x80x94C(O)xe2x80x94NHxe2x80x94,
g) (C1-C2)alkyl-Oxe2x80x94C(O)xe2x80x94,
h) HOxe2x80x94CH2xe2x80x94,
i) CH3Oxe2x80x94NHxe2x80x94,
j) (C1-C3)alkyl-O2Cxe2x80x94
k) CH3xe2x80x94C(O)xe2x80x94,
l) CH3xe2x80x94C(O)xe2x80x94CH2xe2x80x94, 
A1 and A2 taken together are: 
b) oxe2x95x90, or 
wherein R102 is
a) Hxe2x80x94,
b) CH3xe2x80x94,
c) phenyl-CH2xe2x80x94, or
d) CH3C(O)xe2x80x94;
wherein R103 is
a) (C1-C3)alkyl-, or
b) phenyl-;
wherein R104 is
a) Hxe2x80x94, or
b) HOxe2x80x94;
wherein R105 is
a) Hxe2x80x94,
b) (C1-C3)alkylxe2x80x94,
c) CH2xe2x95x90CHxe2x80x94CH2xe2x80x94, or
d) CH3xe2x80x94Oxe2x80x94(CH2)2xe2x80x94;
wherein R106 is
a) CH3xe2x80x94C(O)xe2x80x94,
b) Hxe2x80x94C(O)xe2x80x94,
c) Cl2CHxe2x80x94C(O)xe2x80x94,
d) HOCH2xe2x80x94C(O)xe2x80x94,
e) CH3SO2xe2x80x94, 
g) F2CHC(O)xe2x80x94, 
i) H3Cxe2x80x94C(O)xe2x80x94Oxe2x80x94CH2xe2x80x94C(O)xe2x80x94,
j) Hxe2x80x94C(O)xe2x80x94Oxe2x80x94CH2xe2x80x94C(O)xe2x80x94, 
l) HCxe2x89xa1Cxe2x80x94CH2Oxe2x80x94CH2xe2x80x94C(O)xe2x80x94, or
m) phenyl-CH2xe2x80x94Oxe2x80x94CH2xe2x80x94C(O)xe2x80x94;
wherein R107 is
a) R102Oxe2x80x94C(R110)(R111)xe2x80x94C(O)xe2x80x94,
b) R103Oxe2x80x94C(O)xe2x80x94,
c) R108xe2x80x94C(O)xe2x80x94, 
f) H3Cxe2x80x94C(O)xe2x80x94(CH2)2xe2x80x94C(O)xe2x80x94,
g) R109xe2x80x94SO2xe2x80x94, 
i) HOxe2x80x94CH2xe2x80x94C(O)xe2x80x94,
j) R116xe2x80x94(CH2)2xe2x80x94,
k) R113xe2x80x94C(O)xe2x80x94Oxe2x80x94CH2xe2x80x94C(O)xe2x80x94,
l) (CH3)2Nxe2x80x94CH2xe2x80x94C(O)xe2x80x94NHxe2x80x94,
m) NCxe2x80x94CH2xe2x80x94,
n) F2xe2x80x94CHxe2x80x94CH2xe2x80x94, or
o) R150 R151NSO2 
wherein R108 is
a) Hxe2x80x94,
b) (C1-C4)alkyl,
c) aryl xe2x80x94(CH2)p,
d) ClH2Cxe2x80x94,
e) Cl2HCxe2x80x94,
f) FH2Cxe2x80x94,
g) F2HCxe2x80x94,
h) (C3-C6)cycloalkyl, or
i) CNCH2xe2x80x94.
wherein R109 is
a) alkylC1-C4,
b) xe2x80x94CH2Cl
c) xe2x80x94CH2CHxe2x95x90CH2,
d) aryl, or
e) xe2x80x94CH2CN;
wherein R110 and R111 are independently
a) Hxe2x80x94,
b) CH3xe2x80x94; or
wherein R112 is
a) Hxe2x80x94,
b) CH3Oxe2x80x94CH2Oxe2x80x94CH2xe2x80x94, or
c) HOCH2xe2x80x94;
wherein R113 is
a) CH3xe2x80x94,
b) HOCH2xe2x80x94,
c) (CH3)2N-phenyl, or
d) (CH3)2Nxe2x80x94CH2xe2x80x94;
wherein R114 is
a) HOxe2x80x94,
b) CH3Oxe2x80x94,
c) H2Nxe2x80x94,
d) CH3Oxe2x80x94C(O)xe2x80x94Oxe2x80x94,
e) CH3xe2x80x94C(O)xe2x80x94Oxe2x80x94CH2xe2x80x94C(O)xe2x80x94Oxe2x80x94,
f) phenyl-CH2xe2x80x94Oxe2x80x94CH2xe2x80x94C(O)xe2x80x94Oxe2x80x94,
g) HOxe2x80x94(CH2)2xe2x80x94Oxe2x80x94,
h) CH3Oxe2x80x94CH2xe2x80x94Oxe2x80x94(CH2)2xe2x80x94Oxe2x80x94, or
i) CH3Oxe2x80x94CH2xe2x80x94Oxe2x80x94;wherein R113 is
a) CH3xe2x80x94,
b) HOCH2xe2x80x94,
c) (CH3)2N-phenyl, or
d) (CH3)2Nxe2x80x94CH2xe2x80x94;
wherein R115 is
a) Hxe2x80x94, or
b) Clxe2x80x94;
wherein R116 is
a) HOxe2x80x94
b) CH3Oxe2x80x94, or
c) F;
wherein R150 and R151 are each H or alkyl C1-C4 or R150 and R151 taken together with the nitrogen atom to which each is attached form a monocyclic heterocyclic ring having from 3 to 6 carbon atoms;
B is an unsaturated 4-atom linker having one nitrogen and three carbons;
M is
a) H,
b) C1-8 alkyl,
c) C3-8 cycloalkyl,
d) xe2x80x94(CH2)mOR13, or
e) xe2x80x94(CH2)hxe2x80x94NR21R22;
Z is
a) O,
b) S, or
c) NM;
W is
a) CH,
b) N, or
c) S or O when Z is NM;
Y is
a) H,
b) F,
c) Cl,
d) Br,
e) C1-3 alkyl, or
f) NO2;
X is
a) H,
b) xe2x80x94CN,
c) OR27,
d) halo,
e) NO2,
f) tetrazoyl,
g) xe2x80x94SH,
h) xe2x80x94S(xe2x95x90O)iR4,
i) xe2x80x94S(xe2x95x90O)2xe2x80x94Nxe2x95x90S(O)jR5R6,
j) xe2x80x94SC(xe2x95x90O)R7,
k) xe2x80x94C(xe2x95x90O)R25,
l) xe2x80x94C(xe2x95x90O)NR27R28,
m) xe2x80x94C(xe2x95x90NR29)R25,
n) xe2x80x94C(R25)(R28)xe2x80x94OR13,
o) xe2x80x94C(R25)(R28)xe2x80x94OC(xe2x95x90O)R13,
p) xe2x80x94C(R28)(OR13)xe2x80x94(CH2)hxe2x80x94NR27R28,
q) xe2x80x94NR27R28,
r) xe2x80x94N(R27)C(xe2x95x90O)R7,
s) xe2x80x94N(R27)xe2x80x94S(xe2x95x90O)iR7,
t) xe2x80x94C(OR14)(OR15)R28,
u) xe2x80x94C(R25)(R16)xe2x80x94NR27R26, or
v) C1-8 alkyl substituted with one or more halos, OH, xe2x95x90O other than at alpha position, xe2x80x94S(xe2x95x90O)iR17, xe2x80x94NR27R28, C2-5 alkenyl, C2-5 alkynyl, or C3-8 cycloalkyl;
R4, R5, R6, R7, R13, R14, R15, R16, and R17 are the same as defined above;
R25 is
a) H,
b) C1-8 alkyl optionally substituted with one or more halos, C3-8 cycloalkyl, C1-4 alkyl substituted with one or more of xe2x80x94S(xe2x95x90O)iR17, xe2x80x94OR13, or OC(xe2x95x90O)R13, NR27R28, or
c) C2-5 alkenyl optionally substituted with CHO, or CO2R13;
R26 is
a) R28, or
b) NR27N28;
R27 and R28 at each occurrence are the same or different and are
a) H,
b) C1-8 alkyl,
c) C3-8 cycloalkyl,
d) xe2x80x94(CH2)mOR13,
e) xe2x80x94(CH2)hxe2x80x94NR21R22, or
f) R27 and R28 taken together are xe2x80x94(CH2)2O(CH2)2xe2x80x94, xe2x80x94(CH2)hCH(COR7)xe2x80x94, or xe2x80x94(CH2)2N(CH2)2(R7);
R29 is
a) xe2x80x94NR27R28,
b) xe2x80x94OR27, or
c) xe2x80x94NHC(xe2x95x90O)R28;
wherein R30 is
a) H,
b) C1-8 alkyl optionally substituted with one or more halos, or
c) C1-8 alkyl optionally substituted with one or more OH, or C1-6 alkoxy;
wherein E is
a) NR39,
b) xe2x80x94S(xe2x95x90O)i, or
c) O;
R38 is
a) H,
b) C1-6 alkyl,
c) xe2x80x94(CH2)q-aryl, or
d) halo;
R39 is
a) H,
b) C1-6 alkyl optionally substituted with one or more OH, halo, or xe2x80x94CN,
c) xe2x80x94(CH2)q-aryl,
d) xe2x80x94CO2R40,
e) xe2x80x94COR41,
f) xe2x80x94C(xe2x95x90O)xe2x80x94(CH2)qxe2x80x94C(xe2x95x90O)R40,
g) xe2x80x94S(xe2x95x90O)2xe2x80x94C1-6 alkyl,
h) xe2x80x94S(xe2x95x90O)2xe2x80x94(CH2)q-aryl, or
i) xe2x80x94(Cxe2x95x90O)j-Het;
R40 is
a) H,
b) C1-6 alkyl optionally substituted with one or more OH, halo, or xe2x80x94CN,
c) xe2x80x94(CH2)q-aryl, or
d) xe2x80x94(CH2)qxe2x80x94OR42;
R41 is
a) C1-6 alkyl optionally substituted with one or more OH, halo, or xe2x80x94CN,
b) xe2x80x94(CH2)q-aryl, or
c) xe2x80x94(CH2)qxe2x80x94OR42;
R42 is
a) H,
b) C1-6 alkyl,
c) xe2x80x94(CH2)q-aryl, or
d) xe2x80x94C(xe2x95x90O)xe2x80x94C1-6 alkyl;
aryl is
a) phenyl,
b) pyridyl, or
c) napthyl; a to c optionally substituted with one or more halo, xe2x80x94CN, OH, SH, C1-6 alkyl, C1-6 alkoxy, or C1-6 alkylthio;
wherein R43 is
a) H,
b) C1-2 alkyl,
c) F, or
d) OH;
R44 is
a) H,
b) CF3,
c) C1-3alkyl optionally substituted with one or more halo,
d) phenyl optionally substituted with one or more halo,
e) R44 and R45 taken together are a 5-, 6-, or 7-membered ring of the formula, 
f) R44 and R45 taken together are xe2x80x94(CH2)kxe2x80x94, when R46 is an electron-withdrawing group;
R45 and R46 at each occurrence are the same or different and are
a) an electron-withdrawing group,
b) H,
c) CF3,
d) C1-3 alkyl optionally substituted with one halo,
e) phenyl, provided at least one of R45 or R46 is an electron-withdrawing group, or
f) R45 and R46 taken together are a 5-, 6-, 7-membered ring of the formula 
U is
a) CH2,
b) O,
c) S, or
d) NR47;
R47 is
a) H, or
b) C1-5 alkyl;
wherein R48 is
a) carboxyl,
b) halo,
c) xe2x80x94CN,
d) mercapto,
e) formyl,
f) CF3,
g) xe2x80x94NO2,
h) C1-6 alkoxy,
i) C1-6 alkoxycarbonyl,
j) C1-6 alkythio,
k) C1-6 acyl,
l) xe2x80x94NR49 R50,
m) C1-6 alkyl optionally substituted with OH, C1-5 alkoxy, C1-5 acyl, or xe2x80x94NR49R50,
n) C2-8 alkenylphenyl optionally substituted with one or two R51,
o) phenyl optionally substituted with one or two R51,
p) a 5-, or 6-membered (un)saturated heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, optionally substituted with one or two R51, or 
R49 and R50 at each occurrence are the same or different and are
a) H,
b) C1-4 alkyl,
c) C5-6 cycloalkyl, or
d) R49 and R50 taken together with the nitrogen atom is a 5-, 6-membered saturated heterocyclic moiety which optionally has a further hetero atom selected from the group consisting of S, N, and O, and can in turn be optionally substituted with, including on the further nitrogen atom, C1-3 alkyl, or C1-3 acyl;
R51 is
a) carboxyl,
b) halo,
c) xe2x80x94CN,
d) mercapto,
e) formyl,
f) CF3,
g) xe2x80x94NO2,
h) C1-6 alkoxy,
i) C1-6 alkoxycarbonyl,
j) C1-6 alkythio,
k) C1-6 acyl,
l) C1-6 alkyl optionally substituted with OH, C1-5 alkoxy, C1-5 acyl, or xe2x80x94NR49R50,
m) phenyl,
n) xe2x80x94C(xe2x95x90O)NR52 R53,
o) xe2x80x94NR49R50,
p) xe2x80x94N(R52)(xe2x80x94SO2R54),
q) xe2x80x94SO2xe2x80x94NR52R53, or
r) xe2x80x94S(xe2x95x90O)iR54;
R52 and R53 at each occurrence are the same or different and are
a) H,
b) C1-6 alkyl, or
c) phenyl;
R54 is
a) C1-4 alkyl, or
b) phenyl optionally substituted with C1-4 alkyl;
wherein R55 is
a) carboxyl,
b) halo,
c) xe2x80x94CN,
d) mercapto,
e) formyl,
f) CF3,
g) xe2x80x94NO2,
h) C1-6 alkoxy,
i) C1-6 alkoxycarbonyl,
j) C1-6 alkylthio
k) C1-6 acyl,
l) xe2x80x94NR56 R57,
m) C1-6 alkyl optionally substituted with OH, C1-5 alkoxy, C1-5 acyl, or xe2x80x94NR56R57,
n) C2-8 alkenylphenyl optionally substituted with one or two R58,
o) phenyl optionally substituted with one or two R58,
p) a 5- or 6-membered (un)saturated heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, optionally substituted with one or two R58, or 
R56 and R57 at each occurrence are the same or different and are
a) H,
b) formyl,
c) C1-4 alkyl,
d) C1-4 acyl,
e) phenyl,
f) C3-6 cycloalkyl, or
g) R56 and R57 taken together with the nitrogen atom is a 5-, 6-membered saturated heterocyclic moiety which optionally has a further hetero atom selected from the group consisting of S, N, and O, and can in turn be optionally substituted with, including on the further nitrogen atom, phenyl, pyrimidyl, C1-3 alkyl, or C1-3 acyl; 
R58 is
a) carboxyl,
b) halo,
c) xe2x80x94CN,
d) mercapto,
e) formyl,
f) CF3,
g) xe2x80x94NO2,
h) C1-6 alkoxy,
i) C1-6 alkoxycarbonyl,
j) C1-6 alkythio,
k) C1-6 acyl,
l) phenyl,
m) C1-6 alkyl optionally substituted with OH, azido, C1-5 alkoxy, C1-5 acyl, xe2x80x94NR65R66, xe2x80x94SR67, xe2x80x94Oxe2x80x94SO2R68, or 
n) xe2x80x94C(xe2x95x90O)NR59 R60,
o) xe2x80x94NR56R57,
p) xe2x80x94N(R59)(xe2x80x94SO2R54),
q) xe2x80x94SO2xe2x80x94NR59R60,
r) xe2x80x94S(xe2x95x90O)iR54,
s) xe2x80x94CHxe2x95x90Nxe2x80x94R61, or
t) xe2x80x94CH(OH)xe2x80x94SO3R64;
R54 is the same as defined above;
R59 and R60 at each occurrence are the same or different and are
a) H,
b) C1-6 alkyl,
c) phenyl, or
d) tolyl;
R61 is
a) OH,
b) benzyloxy,
c) xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94NH2,
d) xe2x80x94NHxe2x80x94C(xe2x95x90S)xe2x80x94NH2, or
e) xe2x80x94NHxe2x80x94C(xe2x95x90NH)xe2x80x94NR62R63;
R62 and R63 at each occurrence are the same or different and are
a) H, or
b) C1-4 alkyl optionally substituted with phenyl or pyridyl;
R64 is
a) H, or
b) a sodium ion;
R65 and R66 at each occurrence are the same or different and are
a) H,
b) formyl,
c) C1-4 alkyl,
d) C1-4 acyl,
e) phenyl,
f) C3-6 cycloalkyl,
g) R65 and R66 taken together are a 5-, 6-membered saturated heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, optionally substituted with, including on the nitrogen atom, phenyl, pyrimidyl, C1-3 alkyl, or C1-3 acyl,
h) xe2x80x94P(O)(OR70)(OR71), or
i) xe2x80x94SO2xe2x80x94R72;
R67 is 
R68 is C1-3 alkyl;
R69 is
a) C1-6 alkoxycarbonyl, or
b) carboxyl;
R70 and R71 at each occurrence are the same or different and are
a) H, or
b) C1-3 alkyl;
R72 is
a) methyl,
b) phenyl, or
c) tolyl;
wherein K is
a) O, or
b) S;
R73, R74, R75, R76, and R77 at each occurrence are the same or different and are
a) H,
b) carboxyl,
c) halo,
d) xe2x80x94CN,
e) mercapto,
f) formyl,
g) CF3,
h) xe2x80x94NO2,
i) C1-6 alkoxy,
j) C1-6 alkoxycarbonyl,
k) C1-6 alkythio,
l) C1-6 acyl,
m) xe2x80x94NR78 R79,
n) C1-6 alkyl optionally substituted with OH, C1-5 alkoxy, C1-5 acyl, xe2x80x94NR78R79, xe2x80x94N(phenyl)(CH2xe2x80x94CH2xe2x80x94OH), xe2x80x94Oxe2x80x94CH(CH3)(OCH2CH3), or xe2x80x94O-phenyl-[paraxe2x80x94NHC(xe2x95x90O)CH3],
o) C2-8 alkenylphenyl optionally substituted with R51,
p) phenyl optionally substituted with R51, or
q) a 5-, or 6-membered (un)saturated heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, optionally substituted with R51,;
R51 is the same as defined above;
R78 and R79 at each occurrence are the same or different and are
a) H,
b) C1-4 alkyl,
c) phenyl, or
d) R78 and R79 taken together with the nitrogen atom is a 5-, 6-membered saturated heterocyclic moiety which optionally has a further hetero atom selected from the group consisting of S, N, and O, and can in turn be optionally substituted with, including on the further nitrogen atom, C1-3 alkyl, or C1-3 acyl;
wherein T is
a) O,
b) S, or
c) SO2;
R75, R76, and R77 are the same as defined above;
R80 is
a) H,
b) formyl,
c) carboxyl,
d) C1-6 alkoxycarbonyl,
e) C1-8 alkyl,
f) C2-8 alkenyl,
xe2x80x83wherein the substituents (e) and (f) can be optionally substituted with OH, halo, C1-6 alkoxy, C1-6 acyl, C1-6 alkylthio or C1-6 alkoxycarbonyl, or phenyl optionally substituted with halo,
g) an aromatic moiety having 6 to 10 carbon atoms optionally substituted with carboxyl, halo, xe2x80x94CN, formyl, CF3, xe2x80x94NO2, C1-6 alkyl, C1-6 alkoxy, C1-6 acyl, C1-6 alkylthio, or C1-6 alkoxycarbonyl;
h) xe2x80x94NR81R82,
i) xe2x80x94OR90,
j) xe2x80x94S(xe2x95x90O)ixe2x80x94R91,
k) xe2x80x94SO2xe2x80x94N(R92)(R93), or
l) a radical of the following formulas:
R81 and R82 at each occurrence are the same or different and are
a) H,
b) C3-6 cycloalkyl,
c) phenyl,
d) C1-6 acyl,
e) C1-8 alkyl optionally substituted with OH, C1-6 alkoxy which can be substituted with OH, a 5-, or 6-membered aromatic heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, phenyl optionally substituted with OH, CF3, halo, xe2x80x94NO2, C1-4 alkoxy, xe2x80x94NR83R84, or 
V is
a) O,
b) CH2, or
c) NR87;
R83 and R84 at each occurrence are the same or different and are
a) H, or
b) C1-4 alkyl;
R85 is
a) OH,
b) C1-4 alkoxy, or
c) xe2x80x94NR88 R89;
R86 is
a) H, or
b) C1-7 alkyl optionally substituted with indolyl, OH, mercaptyl, imidazoly, methylthio, amino, phenyl optionally substituted with OH, xe2x80x94C(xe2x95x90O)xe2x80x94NH2, xe2x80x94CO2H, or xe2x80x94C(xe2x95x90NH)xe2x80x94NH2;
R87 is
a) H,
b) phenyl, or
c) C1-6 alkyl optionally substituted by OH;
R88 and R89 at each occurrence are the same or different and are
a) H,
b) C1-5 alkyl
c) C3-6 cycloalky, or
d) phenyl;
R90 is
a) C1-8 alkyl optionally substituted with C1-6 alkoxy or C1-6 hydroxy, C3-6 cycloalkyl, a 6-membered aromatic optionally benzo-fused heterocyclic moiety having one to three nitrogen atoms, which can in turn be substituted with one or two xe2x80x94NO2, CF3, halo, xe2x80x94CN, OH, C1-5 alkyl, C1-5 alkoxy, or C1-5 acyl; 
c) phenyl, or
d) pyridyl;
R91 is
a) C1-16 alkyl,
b) C2-16 alkenyl,
xe2x80x83wherein the substituents (a) and (b) can be optionally substituted with C1-6 alkoxycarbonyl, or a 5-, 6-, 7-membered aromatic heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O,
c) an aromatic moiety having 6 to 10 carbon atoms, or
d) a 5-, 6-, 7-membered aromatic heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O,
xe2x80x83wherein the substituents (c) and (d) can be optionally substituted with carboxyl, halo, xe2x80x94CN, formyl, CF3, xe2x80x94NO2, C1-6 alkyl, C1-6 alkoxy, C1-6 acyl, C1-6 alkylthio, or C1-6 alkoxycarbonyl;
R92 and R93 at each occurrence are the same or different and are
a) H,
b) phenyl,
c) C1-6 alkyl, or
d) benzyl;
R94 and R95 at each occurrence are the same or different and are
a) H,
b) OH,
c) C1-6 alkyl optionally substituted with xe2x80x94NR83 R84, or
d) R94 and R95 taken together are xe2x95x90O;
R96 is
a) an aromatic moiety having 6 to 10 carbon atoms,
b) a 5-, or 6-membered aromatic optionally benzo-fused heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O,
xe2x80x83wherein the substituents (a) and (b) which can in turn be substituted with one or three xe2x80x94NO2, CF3, halo, xe2x80x94CN, OH, phenyl, C1-5 alkyl, C1-5 alkoxy, or C1-5 acyl,
c) morpholinyl,
d) OH,
e) C1-6 alkoxy,
f) xe2x80x94NR83R84,
g) xe2x80x94C(xe2x95x90O)xe2x80x94R97, or 
R97 is
a) morpholinyl,
b) OH, or
c) C1-6 alkoxy;
h is 1, 2, or 3;
i is 0, 1, or 2;
j is 0 or 1;
k is 3, 4, or 5;
l is 2 or 3;
m is 4 or 5;
n is 0, 1, 2, 3, 4, or 5;
p is 0, 1, 2, 3, 4, or 5; with the proviso that n and p together are 1, 2, 3, 4, or 5;
q is 1, 2, 3, or 4;
r is 2, 3, or 4;
t is 0, 1, 2, 3, 4, 5, or 6;
u is 1 or 2;
w is 0, 1, 2, or 3.
The new compounds of the invention can be prepared using known compounds and intermediates of oxzolidinones, isoxazolines and butyolactones as intermediates and synthetic methods known in the art. Thioamides of the invention can typically be prepared by the reaction of the corresponding amide with Lawesson""s reagent.
Compounds disclosed in the following publications are suitable intermediates for preparation of the compounds of this invention and are hereby incorporated by reference for their disclosure of suitable compounds that can be converted to the subject thiocarbonyl derivatives.
U.S. Pat. Nos. 5,225,565; 5,182,403; 5,164,510; 5,247,090; 5,231,188; 5,565,571; 5,547,950; and 5,523,403.
PCT Application and publications PCT/US93/04850, WO94/01110; PCT/US94/08904, WO 95/07271; PCT/US95/02972, WO95/25106; PCT/US95/10992, WO96/13502; PCT/US96/05202, WO96/35691; PCT/US96/12766; PCT/US96/13726; PCT/US96/14135; PCT/US96/17120; PCT/US96/19149; PCT/US97/01970; PCT/US95/12751, WO96/15130; and PCT/US96/00718, WO96/23788.
Chemical conversion techniques for converting various intermediates having a CH2NH2 on the oxazolidinone ring to CH2NHxe2x80x94C(S)xe2x80x94CH3 is disclosed by Hartke, K., Barrmeyer, S., J. prakt. Chem. 1996, 338, 251-6. Similarly, conversion of CH2NHC(xe2x95x90O)CH3 to CH2NHC(S)NHCH3 is reported by Cava, M. P.; Levinson, M. I., Thionation Reactions of Lawesson""s Reagents, Tetrahedron 1985, 41, 5061-87.
For the purpose of the present invention, the carbon content of various hydrocarbon containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix Ci-j defines the number of carbon atoms present from the integer xe2x80x9cixe2x80x9d to the integer xe2x80x9cjxe2x80x9d, inclusive. Thus, C1-4 alkyl refers to alkyl of 1-4 carbon atoms, inclusive, or methyl, ethyl, propyl, butyl and isomeric forms thereof.
The terms xe2x80x9cC1-2 alkylxe2x80x9d, xe2x80x9cC1-3 alkylxe2x80x9d, xe2x80x9cC1-4 alkylxe2x80x9d, xe2x80x9cC1-5 alkylxe2x80x9d, xe2x80x9cC1-6 alkylxe2x80x9d, xe2x80x9cC1-8 alkylxe2x80x9d, and xe2x80x9cC1-16 alkylxe2x80x9d refer to an alkyl group having one to two, one to three, one to four, one to five, one to six, one to eight, or one to sixteen carbon atoms respectively such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl and their isomeric forms thereof.
The terms xe2x80x9cC2-4 alkenylxe2x80x9d, xe2x80x9cC2-5 alkenylxe2x80x9d, xe2x80x9cC2-8 alkenylxe2x80x9d, xe2x80x9cC2-14 alkenylxe2x80x9d and xe2x80x9cC2-16 alkenylxe2x80x9d refer to at least one double bond alkenyl group having two to four, two to five, two to eight, two to fourteen, or two to sixteen carbon atoms, respectively such as, for example, ethenyl, propenyl, butenyl, pentenyl, pentdienyl, hexenyl, hexdienyl, heptenyl, heptdienyl, octenyl, octdienyl, octatrienyl, nonenyl, nonedienyl, nonatrienyl, undecenyl, undecdienyl, dodecenyl, tridecenyl, tetradecenyl and their isomeric forms thereof.
The terms xe2x80x9cC2-5 alkynylxe2x80x9d, xe2x80x9cC2-8 alkynylxe2x80x9d, and xe2x80x9cC2-10 alkynylxe2x80x9d refer to at least one triple bond alkynyl group having two to five, two to eight, or two to ten carbon atoms respectively such as, for example, ethynyl, propynyl, butynyl, pentynyl, pentdiynyl, hexynyl, hexdiynyl, heptynyl, heptdiynyl, octynyl, octdiynyl, octatriynyl, nonynyl, nonediynyl, nonatriynyl and their isomeric forms thereof.
The terms xe2x80x9cC3-4 cycloalkylxe2x80x9d, xe2x80x9cC3-6 cycloalkylxe2x80x9d, xe2x80x9cC5-6 cycloalkylxe2x80x9d, and xe2x80x9cC3-8 cycloalkylxe2x80x9d refer to a cycloalkyl having three to four, three to six, five to six, or three to eight carbon atoms respectively such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and their isomeric forms thereof.
The terms xe2x80x9cC1-4 alkoxyxe2x80x9d, xe2x80x9cC1-6 alkoxyxe2x80x9d, and xe2x80x9cC1-8 alkoxyxe2x80x9d refer to an alkyl group having one to four, one to six, or one to eight carbon atoms respectively attached to an oxygen atom such as, for example, methoxy, ethoxy, propyloxy, butyloxy, pentyloxy, hexyloxy, heptyloxy, or octyloxy and their isomeric forms thereof.
The terms xe2x80x9cC1-6 alkylaminoxe2x80x9d, and xe2x80x9cC1-8 alkylaminoxe2x80x9d refer to an alkyl group having one to six, or one to eight carbon atoms respectively attached to an amino moiety such as, for example, methylamino, ethylamino, propylamino, butylamino, pentylamino, hexylamino, heptylamino, or octoylamino and their isomeric forms thereof.
The terms xe2x80x9cC1-6 dialkylaminoxe2x80x9d, and xe2x80x9cC1-8 dialkylaminoxe2x80x9d refer to two alkyl groups having one to six, or one to eight carbon atoms respectively attached to an amino moiety such as, for example, dimethylamino, methylethylamino, diethylamino, dipropylamino, methypropylamino, ethylpropylamino, dibutylamino, dipentylamino, dihexylamino, methylhecylamino, diheptylamino, or dioctoylamino and their isomeric forms thereof.
The terms xe2x80x9cC1-3 acylxe2x80x9d, xe2x80x9cC1-4 acylxe2x80x9d, xe2x80x9cC1-5 acylxe2x80x9d, xe2x80x9cC1-6 acylxe2x80x9d, xe2x80x9cC1-8 acylxe2x80x9d, and xe2x80x9cC2-8 acylxe2x80x9d refer to a carbonyl group having an alkyl group of one to three, one to four, one to five, one to six, one to eight, or two to eight carbon atoms.
The terms xe2x80x9cC1-4 alkoxycarbonylxe2x80x9d, xe2x80x9cC1-6 alkoxycarbonylxe2x80x9d, and xe2x80x9cC1-8 alkoxycarbonylxe2x80x9d refer to an ester group having an alkyl group of one to four, one to six, or one to eight carbon atoms.
The term xe2x80x9cC1-8 alkyl phenylxe2x80x9d refers to an alkyl group having one to eight carbon atoms and isomeric forms thereof which is substituted with at least one phenyl radical.
The term xe2x80x9cC2-8 alkenyl phenylxe2x80x9d refers to a at least one double bond alkenyl group having one to eight carbon atoms and isomeric forms thereof which is substituted with at least one phenyl radical.
The term xe2x80x9cC1-8 alkyl pyridylxe2x80x9d refers to an alkyl group having one to eight carbon atoms and isomeric forms thereof which is substituted with at least one pyridyl radical.
The term xe2x80x9cC1-8 hydroxylxe2x80x9d refers to an alkyl group having one to eight carbon atoms and isomeric forms thereof attached to a hydroxy group.
The term xe2x80x9cC1-8 alkylsulfonylxe2x80x9d refers to an alkyl group having one to eight carbon atoms and isomeric forms thereof attached to a SO2 moiety.
The term xe2x80x9cC1-6 alkylthioxe2x80x9d refers to an alkyl group having one to six carbon atoms and isomeric forms thereof attached to a sulfur atom.
The term xe2x80x9cHetxe2x80x9d refers to 5 to 10 membered saturated, unsaturated or aromatic heterocyclic rings containing one or more oxygen, nitrogen, and sulfur forming such groups as, for example, pyridine, thiophene, furan, pyrazoline, pyrimidine, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 3-pyrazinyl, 2-quinolyl, 3-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 2-quinazolinyl, 4-quinazolinyl, 2-quinoxalinyl, 1-phthalazinyl, 4-oxo-2-imidazolyl, 2-imidazolyl, 4-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 4-oxo-2-oxazolyl, 5-oxazolyl, 4,5,-dihydrooxazole, 1,2,3-oxathiole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazole, 4-isothiazole, 5-isothiazole, 2-indolyl, 3-indolyl, 3-indazolyl, 2-benzoxazolyl, 2-benzothiazolyl, 2-benzimidazolyl, 2-benzofuranyl, 3-benzofuranyl, benzoisothiazole, benzisoxazole, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 3-isopyrrolyl, 4-isopyrrolyl, 5-isopyrrolyl, 1,2,3,-oxathiazole-1-oxide, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 5-oxo-1,2,4-oxadiazol-3-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 3-oxo-1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-5-yl, 2-oxo-1,3,4-thiadiazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,2,3,4-tetrazol-5-yl, 5-oxazolyl, 1-pyrrolyl, 1-pyrazolyl, 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, 1-tetrazolyl, 1-indolyl, 1-indazolyl, 2-isoindolyl, 7-oxo-2-isoindolyl,1-purinyl, 3-isothiazolyl, 4-isothiazolyl and 5-isothiazolyl, 1,3,4,-oxadiazole, 4-oxo-2-thiazolinyl, or 5-methyl-1,3,4-thiadiazol-2-yl, thiazoledione, 1,2,3,4-thiatriazole, 1,2,4-dithiazolone. Each of these moieties may be substituted as appropriate.
The term halo refers to fluoro, chloro, bromo, or iodo.
The compounds of the present invention can be converted to their salts, where appropriate, according to conventional methods.
The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refers to acid addition salts useful for administering the compounds of this invention and include hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate, lactate, mesylate, maleate, malate, succinate, tartrate, citric acid, 2-hydroxyethyl sulfonate, fumarate and the like. These salts may be in hydrated form.
When Q is the structure of 
the dotted line in the heterocyclic ring means that this bond can be either single or double. In the case where the dotted line is a double bond, the R39 group will not be present.
The compounds of Formula I of this invention contain a chiral center at C5 of the isoxazoline ring, and as such there exist two enantiomers or a racemic mixture of both. This invention relates to both the enantiomers, as well as mixtures containing both the isomers. In addition, depending on substituents, additional chiral centers and other isomeric forms may be present in any of A or R1 group, and this invention embraces all possible stereoisomers and geometric forms in these groups.
The compounds of this invention are useful for treatment of microbial infections in humans and other warm blooded animals, under both parenteral and oral administration.
The pharmaceutical compositions of this invention may be prepared by combining the compounds of this invention with a solid or liquid pharmaceutically acceptable carrier and, optionally, with pharmaceutically acceptable adjuvants and excipients employing standard and conventional techniques. Solid form compositions include powders, tablets, dispersible granules, capsules, cachets and suppositories. A solid carrier can be at least one substance which may also function as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, tablet disintegrating agent, and encapsulating agent. Inert solid carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, cellulosic materials, low melting wax, cocoa butter, and the like. Liquid form compositions include solutions, suspensions and emulsions. For example, there may be provided solutions of the compounds of this invention dissolved in water and water-propylene glycol and water-polyethylene glycol systems, optionally containing suitable conventional coloring agents, flavoring agents, stabilizers and thickening agents.
Preferably, the pharmaceutical composition is provided employing conventional techniques in unit dosage form containing effective or appropriate amounts of the active component, that is, the compound according to this invention.
The quantity of active component, that is the compound according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the particular application, the potency of the particular compound, the desired concentration. Generally, the quantity of active component will range between 0.5% to 90% by weight of the composition.
In therapeutic use for treating, or combatting, bacterial infections in warm-blooded animals, the compounds or pharmaceutical compositions thereof will be administered orally, parenterally and/or topically at a dosage to obtain and maintain a concentration, that is, an amount, or blood-level of active component in the animal undergoing treatment which will be antibacterially effective. Generally, such antibacterially effective amount of dosage of active component will be in the range of about 0.1 to about 100, more preferably about 3.0 to about 50 mg/kg of body weight/day. It is to be understood that the dosages may vary depending upon the requirements of the patient, the severity of the bacterial infection being treated, and the particular compound being used. Also, it is to be understood that the initial dosage administered may be increased beyond the above upper level in order to rapidly achieve the desired blood-level or the initial dosage may be smaller than the optimum and the daily dosage may be progressively increased during the course of treatment depending on the particular situation. If desired, the daily dose may also be divided into multiple doses for administration, e.g., 2-4 four times per day.
When the compounds according to this invention are administered parenterally, i.e., by injection, for example, by intravenous injection or by other parenteral routes of administration. Pharmaceutical compositions for parenteral administration will generally contain a pharmaceutically acceptable amount of the compound or a soluble salt (acid addition salt or base salt) dissolved in a pharmaceutically acceptable liquid carrier such as, for example, water-for-injection and a buffer to provide a suitably buffered isotonic solution, for example, having a pH of about 3.5-6. Suitable buffering agents include, for example, trisodium orthophosphate, sodium bicarbonate, sodium citrate, N-methylglucamine, L(+)-lysine and L(+)-arginine to name but a few representative buffering agents. The compound of this invention generally will be dissolved in the carrier in an amount sufficient to provide a pharmaceutically acceptable injectable concentration in the range of about 1 mg/mL to about 400 mg/mL of solution. The resulting liquid pharmaceutical composition will be administered so as to obtain the above-mentioned antibacterially effective amount of dosage. The compounds according to this invention are advantageously administered orally in solid and liquid dosage forms.
As a topical treatment an effective amount of Formula I is admixed in a pharmaceutically acceptable gel or cream vehicle that can be applied to the patient""s skin at the area of treatment. Preparation of such creams and gels is well known in the art and can include penetration enhancers.
MIC Test Method
The in vitro MICs of test compounds were determined by a standard agar dilution method. A stock drug solution of each analog is prepared in the preferred solvent, usually DMSO:H2O (1:3). Serial 2-fold dilutions of each sample are made using 1.0 ml aliquots of sterile distilled water. To each 1.0 ml aliquot of drug is added 9 ml of molten Mueller Hinton agar medium. The drug-supplemented agar is mixed, poured into 15xc3x97100 mm petri dishes, and allowed to solidify and dry prior to inoculation.
Vials of each of the test organisms are maintained frozen in the vapor phase of a liquid nitrogen freezer. Test cultures are grown overnight at 35xc2x0 C. on the medium appropriate for the organism. Colonies are harvested with a sterile swab, and cell suspensions are prepared in Trypticase Soy broth (TSB) to equal the turbidity of a 0.5 McFarland standard. A 1:20 dilution of each suspension is made in TSB. The plates containing the drug supplemented agar are inoculated with a 0.001 ml drop of the cell suspension using a Steers replicator, yielding approximately 104 to 105 cells per spot. The plates are incubated overnight at 35xc2x0 C.
Following incubation the Minimum Inhibitory Concentration (MIC xcexcg/ml), the lowest concentration of drug that inhibits visible growth of the organism, is read and recorded. The data is shown in Tables I and II.
As shown in Scheme 1, the intermediates II for the compounds of this invention are also intermediates disclosed in the oxazolidinone patents and published applications hereinabove incorporated by reference. The intermediates IV for this invention are final products (Examples) from the oxazolidinone patents and published applications hereinabove incorporated by reference.
As shown in Scheme 1, Step 1, and illustrated in Example 5, the isothiocyanates III can be conveniently prepared by allowing the amine intermediates (II) to react with 1,1xe2x80x2-thiocarbonyldi-2(1H)-pyridone in solvents such as methylene chloride at 0 to 25xc2x0 C. The thioureas (Ia, Rxe2x80x2xe2x95x90H, alkyl1-4) can then be prepared as shown in Step 2 by the reaction of III with ammonia or the appropriate primary amines in solvents such as 1,4-dioxane or tetrahydrofuran at 0-50xc2x0 C. Alternatively, as illustrated in Example 6 and shown in Step 3, the thioureas can be prepared by allowing II to react with an appropriate isothiocyanate (Rxe2x80x2xe2x80x94Nxe2x95x90Cxe2x95x90S) in solvents such as tetrahydrofuran at 0-50xc2x0 C. Thioamides (Ib, Rxe2x80x3xe2x95x90H, alkyl1-4) are prepared by allowing II to react with an appropriate dithioester (Rxe2x80x2xe2x80x3 Sxe2x80x94C(xe2x95x90S)xe2x80x94Rxe2x80x3, Step 4 as illustrated in Example 4. This reaction is carried out in aqueous-alcoholic solvents at 0-50xc2x0 C. in the presence of an equivalent of an alkali metal hydroxide. This reaction, especially when Rxe2x80x2xe2x80x3 is methyl or ethyl, can be catalyzed by an alkali metal fluoride.
The reaction of II with Rxe2x80x2xe2x80x3xe2x80x94Sxe2x80x94C(S)xe2x80x94Rxe2x80x2xe2x80x3 (Rxe2x80x2xe2x80x3xe2x95x90CH3, C2H5) to give Ib (Step 4) can also be carried out in the presence of a tertiary amine base such as triethylamine in solvents such as THF, dioxane or methylene chloride at 10-50xc2x0 C. for 3-48 hr.
When the reaction conditions are tolerated by the substituents on R (see, for example, Examples 1-3) the thioamides (Ib, Rxe2x80x3xe2x80x94H, alkyl1-4) can also be conveniently prepared (Step 5) by allowing the appropriate amide intermediates (IV) to react with reagents such as 2,4-bis(p-methoxyphenyl)-1,3-dithiadiphosphetane-2,4-disulfide (Lawesson""s Reagent) in 1,4-dioxane, benzene, toluene or tetrahydrofuran at 60-110xc2x0 C.; phosphorus decasulfide and sodium carbonate in tetrahydrofuran at 20-50xc2x0 C. [Brillon, D., Synthetic Communications, 20, 3085 (1990)] or phosphorus decasulfide and sodium fluoride in 1,2-dimethoxyethane at 20-50xc2x0 C. [Hartke, K., Gerber, H.-D., J. Prakt. Chem., 338, 763 (1996)].
Compounds Ic are prepared (Step 6) by allowing II to react first with carbon disulfide and a tertiary amine base such as triethylamine in solvent mixtures containing water and methanol, ethanol or isopropanol at 10-50xc2x0 C. for 5-24 hours. The resulting intermediate is treated with an alkylating agent (Rxe2x80x3xe2x80x3 X where X represents bromo, iodo, alkylsulfonyloxy or arylsulfonyloxy) at 0-30xc2x0 C. to give compounds Ic. In Step 7, compounds Ic are allowed to react with alkali metal alkoxide such as sodium methoxide or potassium ethoxide in the corresponding alkanol as solvent. This reaction is conveniently carried out at the reflux temperature of the alkanol for 1-24 hr. 